\r\n\tThe classic definition of organic chemistry as a study of the structure, properties and reactions of organic compounds is found in the chapters of this book, starting from the composition, structure and properties of organic compounds, continuing with electronic effects, reaction mechanisms, stereochemistry, synthesis and reactivity of functional groups. The book will also address applications of organic compounds as drugs, dyes, food, materials used in nonlinear optics, various techniques. It will also focus on the role of carbohydrates, amino acids, proteins, DNA, lipids, vitamins, enzymes, antioxidants in life processes. \r\n\tThe chapters of this book aim to illustrate the problems of organic chemistry through the various studies presented, which update the knowledge of organic chemistry and its latest applications in various fields of activity.
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1. Introduction
Greenways are linear open spaces such as canals and scenic roads that are set along the riversides, hillsides or valleys, converted to a recreational use along the railways (Little, 1995).
As the last scientific sources about greenways in landscape planning are examined (President’s Commission on Americans Outdoors, 1987; Little, 1990; Flink and Searns, 1993; Smith and Hellmund, 1993) the definition of "designed and managed space networks that are compatible with the concepts of sustainable space use" comes out (Ahern, 1995).
In 1970s, when the decreasing of urban open spaces became clear throughout the country, the greenways planning activities directed to preserving gained importance. Those greenways which need less open space than conventional parks, make possible various recreational activities and form a system of being associated different open and green spaces are supported by authorities and the institutions directed to protecting environment (Arslan et. al., 2007).
The most clear statement on this subject came out by President’s Commission on Americans Outdoors in 1987. The commission sees the greenways as live networks like a giant circulation system. That provides people with access to open spaces close to where they live, and link together the rural and urban spaces in the American Greenways in the USA. Therefore, the commission suggested to generalize greenways which are a vision for the future as a system. It is possible to see more than 660 greenways examples implemented in the USA whose 80 % of its population live in cities (Bueno et. al., 1995).
Commission draws a parallel between the evolution model of greenways and motorways or railway system. According to this idea, the motorways and railways which are firstly formed in small parts, later the left parts of them are networked by planners, being combined in scale of national, state and regional. Similarly, greenways are of various widths and have a network system like main roads and railways junction systems. Just the main difference is the nature has already an existing system infrastructure corridor (Fabos, 1995).
The first serious attempt in Europe is made, in 1997, by establishing European Greenway Association (EGWA). This Association define the greenways as both protecting environmental values and the network of routes that are allocated for only the motorless vehicles (on horseback, bicycling or etc.) in order to increase the health of environmental life, considering integrated management approach (Fig. 1) (European Greenways Association, 2004).
Figure 1.
Salisbury Greenway Bicycle Way/ North Carolina
Greenways are defined differently in both the concept and scope. Since these greenways focus on different aims, their scopes are different (Scudo, 2006). For example, the level of aims of protection, using mainly under protection, protection mainly under using and using (like recreation) affects the forming of greenways.
Two words should be examined to make clear the definition. The full word is “Greenway”. “Green” is defined as forests, riversides, natural spaces like wild life, “way” as a route or an axis. Two words together are depicted as greenway or an axis integrated with landscape (Watson et. al., 2003).
Greenways are a general term of showing linear consistency, linking open and green spaces and providing development into urban texture. There are bicycle passages, wild life routes, improved water sides or a river far from a city or pedestrian axes forested along a bay. Within the urban landscape, greenways brought together two functions. One of them is to form open spaces which are open to public and for recreational uses, and the second one is to ensure to protect and develop natural resources (Vikipedi Özgür Ansiklopedi, 2008).
Greenways are the passages that provide linking the spaces that have the specialty of high natural resource or are of cultural aspects. These greenways are based on both land and water (http://www.chaddsfordpa.net/resources.htm).
Even if their scope is narrow, greenways whose first examples come out in the nineteenth century gave birth as an answer to the needs for the conditions of relevant period, the changing - corrupting process of landscapes in the last century and negative development of cities to the detriment of ecosystems. Changing of conditions, conceptions and tendencies lead to change of the concept and scope of greenways.
In the context of urban planning of nineteenth century, the development process of greenways classified into 3 categories. These are:
First Generation Greenways (the period between1700 and 1960)
Second Generation Greenways (the period between 1960-1985)
Third Generation Greenways (the period after1985)
1.1. First Generation Greenways the period (between1700 and 1960)
First generation greenways are defined as “Green Way” and the first example of special and attractive corridors through the city (Searns, 1995). The axes that link in Europe city spaces and their surrounding are planted, boulevards and at the end of the nineteenth century, the parkways commonly used in the USA are the systems of first examples of these corridors (Ahern, 2004).
Frederick Law Olmsted developed the idea of parkway system which leads to taking shape of current greenways (Kent and Elliott, 1995). The first parkway model started with the designs of Central Park of New York city by Olmsted and Vaux (http://www. umass.edu/greenway/Greenways /2GR-def.html).
In later period, Olmsted and Vaux who are affected by the wide boulevards of Paris and Brussels designed “Prospect Park (Macdonald, 2005). One of the important aspects of this park is its characteristic of rural landscape which is fully different from central park and the general structure of the city.
At the end of the nineteenth century and beginning of the twentieth century, first real greenways came from the system of the open spaces of the main city. This mostly is the network that is formed due to linking spatially linear spaces belong to public. The system is tied to the current topographical and hydrological models in the landscape. The Boston Park system is the most important one of these systems that Frederick Law Olmsted designed (Zube, 1995).
In 1887, The Boston Park System known as “Emerald Necklace” is the first greenway planned in the USA. Newton mentions this park system as parkway. This system that is 25 km length link the cities of Boston, Brooklyn to Cambridge city in Massachusetts State and Charles river to these spaces (Fabos, 2004). Olmsted also named this system as “strip park” known as parkway before (Little, 1995).
While, today, Boston Park system provide mostly recreation, transportation, water quality, flood control, nice view, wildlife, when it was first planned as a model, it was designed for linking the current conserved areas to the ecological greenways. This first design of Olmsted is adopted by various landscape architects (Ahern, 2004).
Charles Eliot, the pioneers of Landscape Architecture, suggested a comprehensive park system for Boston main city region. This corridor combined 6 wide green spaces connected to each other in the slums of main city into 3 big rivers (www.umass.edu/greenway). The suggestion of Eliot that sees rivers and their sides as the complementary of greenway system is important for the planning of greenways.
In nineteenth century, H.W.S. Cleveland, with Theodore Wirth, beside Eliot in the USA, planned greenways network for Minneapolis main city region. This parkway that provides both transportation and walking, picnic and natural hiking and is of 23-mile length is the parkway of Bronx River (Ryder, 1995).
After Bronx River parkway, parkways started to increase with this new trend and the architect Robert Moses who is affected by this trend implemented several parkways such as Hutcheson River Parkway, Taconic Parkway, Saw Mill River Parkway and Cross County Parkway, in Westchester and Bronx, and Henry Hudson Parkway in Manhattan (Arslan et.al., 2007).
The aim of Moses is to form a recreational network for New York people. Because of the transporting easiness of motorcars, as tendency for recreational spaces is getting increased. Moses especially observed that the spaces in Westchester and New Jersey have limited possibility for weekend activities. For this aim, Moses formed the Brooklyn-Queens greenways that link all the rural region which include east river, agricultural fields, sea sides, ponds, rivers and forest areas (Little, 1995).
As well as parkways concept, the green generation concept within the historic development of the greenway idea has an important place. The idea of parkways of Olmsted and Moses became the source to thought of surrounding and zoning the city, developing in the course of time. The first greenway that is The London Plan of Ebenezer Howard is defined as a band limiting the borders of cities and a wide band of 5-mile or more in rural areas (Searns, 1995).
In this period, other landscape architects are Henry Wright and Charles Eliot II who work on greenways. A park design which is 40 mile length and is named as “40-mile circle” by Wright and Eliot II is held up by other greenway planners instead of a big park design in Portland, Oregon. Moreover, that Wright include several landscape elements from river greenways to forest spaces in integrated greenway network is supported by ASLA (American Society of Landscape Architecture) (Fabos, 2004).
Another plan in this period is the first open space plan which was designed by Charles Eliot II for Massachusetts state. The comprehensive plan in statewide was named “Bay Circuit Plans”. This comprehensive plan which is some 250 km length links several wetlands and drainage systems and surrounds Boston city (www.umass.edu/greenway).
The most important development in this period is the coupling national parks and comprehensive recreational areas and parkways and so there will be continuity between the spaces that are protected and used for recreational aim (http://www.nps. gov/aboutus/history.htm). A highlighter example of this is Blue Ridge Parkway along the Appalachian mountain (Fabos, 2004).
1.2. Second Generation Greenways (the period after 1960-1985)
First generation greenways that are parkways included in the open and green space system that links urban and rural spaces are firstly converted into the urban corridors after the second half of twentieth century.
Throughout the 1960s and 1970s, the subjects that support contemporary greenways development process in terms of environmental aspects are divided into two parts. One of them is the increasing of bicycle passages and second is the works of landscape architects in academic area.
Because the harms that motorcars coming out from 1900s do increased towards the second half of twentieth century so the demand for bicycle passage and pedestrian pathways that are motorless traffic routes. The implementation of the bicycle passage and pedestrian pathways that are a part of greenways is practiced several times in the USA and Europe. Throughout the period of 1960s-1970s, bicycle passage and pedestrian pathways named as city pathways supported the environmental conscience because they had had the goals of preserving cultural landscapes, controlling the city development and recreation (Little, 1995).
In this process that environmental conscience was increased, several landscape planning and design works that are linked to greenways would be a basis for the studies and were realized. Phil Lewis determined 220 natural and cultural resources in Wisconsin by “the method of mapping” that he found. Since these resources are especially along the river or drainage spaces, Lewis (1964) named these spaces as “environmental corridors”. Lewis’s mapping, analyzing and evaluating the resources provided a basis for the suggestion plan of “Wisconsin Heritage Pathway”. “The term of environmental corridor” that was created by Lewis to protect river corridors or the spaces environmentally sensitive is used in first greenway/green space system planning in statewide. In this planning process, to protect the spaces that are environmentally sensitive, and river corridors are targeted (Fabos, 2004).
The end of 1960s is the beginning for the term of “Greenway”. In this period, William H. Whyte used the term of “Greenway” for the first time in his book entitled” “The Last Landscape” that he wrote to get rid of motorcar (Bueno et. al., 1995). The first implemented greenway project of Whyte is “Platte River Greenway” in Denver in the mid of 1970s. This corridor, 10 mile length, comprises parks, spaces having natural characteristics, canals and harbour region. There is also a stroll and bicycle route, 2.5 m width (Searns, 1995).
1.3. Third Generation Greenways (The period after 1985)
These greenways targeted to satisfy aesthetical and recreational needs for city dwellers with the beatified axes and corridors in addition to motorless vehicles routes. Thus, both negative effects of urbanization are reduced and alternative corridors that supply influential visual forms and greens for screening the fumes and noises of motorcars are created. This situation contributes to the spiritual healing of urban people (Searns, 1995).
This generation corridors have more comprehensive duties apart from all these characteristics of them. Third generation greenways, beyond meet people need, take on a lot of goals such as preserving habitat, reducing flood harms, increasing water quality, protecting historical sites, education, which are integrated with space and resource management concepts (Mugavin, 2004).
3. Greenways types
Greenways that are a part of a wide network to protect the elements which shows physical continuity in landscape are formed around railways, canals, roads that are along the hillsides and valleys, watersides and rivers.
Main concept is to keep the corridor "green" with the natural vegetation and to connect the interesting points along the river and similar systems to a “way” or line. Greenways are formed directly and indirectly for people benefits and uses. For example, a greenway can provide recreational walks, observing wild life, recognition and evaluation of the environment, river fishing and riverside protecting (Glossary of Bicycle Terms, 2008).
Greenways are divided into 6 groups according to the projections of scientists and planners who work for different goals;
Urban riverside greenways: they are the greenways that are formed by riversides in urban areas. Sometimes, the destroyed riversides which are affected by urban activities can be ameliorated by redevelopment programs. These spaces are thought as a part of greenways (Little, 1995). Beside this definition, not only riversides but the other sources that are linked to water are included greenways (Fig. 2). As a result, the greenways are formed along the water resources such as, flood beds, river corridors and wetlands. The aim of creating these greenways is to protect resources, ameliorate and manage (Ahern, 1995).
Figure 2.
Scioto River Greenway
Recreational greenways: They are the spaces that have characteristics of routes and pathways of various type and go along a very long line (Little, 1995). Beside the natural corridors, canals and railway routes can be examples of that kind of spaces. These ways are formed along the routes and pathways passing through recreational spaces generally linked water and landscape resources which are of high visual value (Fabos, 1995). The recreational focuses in these pathways not only can be both urban and rural but local, regional, national and international (Fig. 3).
Figure 3.
Willamette River Greenway, Oregon
Natural corridors that are of Ecological importance: they are the corridors which are formed by the spaces generally along the rivers, and sometimes valley sides (Little, 1995). These kind of spaces make possible protecting wild life, migrating of species, sustaining biological diversity and natural hiking (Fabos, 1995). Ahern (1995), define ecological corridors as "ones that are linked to biodiversity" (Fig. 4).
Greenways that have visual and historical value: they are the greenways that are attract tourists, provide benefits of economical, educational and visual and supply permanent-seasonal accommodation (Fabos, 1995). They generally are the routes along the road or motorways and the routes rarely along watersides. These routes make possible seeing by getting out of vehicles and pedestrian activities in specific points (Little, 1995). Another important characteristic of these greenways is that they link cultural and historic resources (Ahern, 1995).
Figure 4.
Oconee River Greenway, Athens, Georgia.
The greenways that aim controlling of urban development: these greenways are formed to separate urban and rural areas and control enlargement (Ahern, 1995).
Comprehensive greenways systems and networks: they are formed by linking different kinds of open areas to greenways in urban and regional scale (Little, 1995).
4. The functions and benefits of greenways
Greenways have a lot of functions such as protecting water sources, reducing pollution, increasing river side habitat and biodiversity, reducing flood harms, providing recreational opportunity, supplying environmental education, alleviating noise, enhancing micro-climatical effects of both cooling and decreasing pollution and reducing riverside erosion (Bischoff, 1995).
It is possible to divide the functions of greenways into two groups as rural and urban. Within the developing urban landscape, greenways have to functions: one of them is to create open spaces for people\'s easy reach (public access) and recreational uses and second to provide protecting and developing natural resources which are still present nowadays. In this context, the greenways that tie in with many various linear open spaces in cities and so provide developing into the textures of cities can be a bicycle passage wildlife routes, urban riverside corridor etc. These urban corridors take on some various duties such as answering to the increasing of people interest for their outside recreation, protecting the areas of habitat and wildlife, balancing between the air pollution and excessive heat changes and controlling urban development (Watson et. al., 2003).
One of the key functions of greenways is a special way that integrates the uses suitable for each other and separates the unsuitable ones from each other.
Greenways provide many benefits that increase quality of public life with using spaces for multiple goals. The recreational, ecological, environmental, cultural, aesthetical, educational and economical benefits are obtained from developing and protecting greenways.
4.1. Environmental benefits
The ecological characteristics of greenways make possible sustain the life of plants and animals, and cause bio-diversity to increase and be protected (Ndubisi et.al., 1995).
Several scientists believe that disintegrating of habitat is the most threatening factor to biologic diversity among the factors such as global warming, extracting metals, grazing, urban development. Disintegrating stems from the changes that human beings make. The structures like roads, canals or the activities such as agricultural development and deforesting prevent the species from their free movement. Ecologists advocate that beside the reducing obstacles, landscape greenways should be created to solve the problems. These linear connections combined habitat parts to make link species, populations and ecological processes (Bueno et. al., 1995).
Greenways take on important duties that are of urban ecological systems. They are important to protect present natural areas hence urban ecological system for future urban development
Greenways are like an open air class. They especially provide information about the importance of the natural environment with the children schooled (Searns, 1995).
4.3. Economical benefits
The economical benefits of greenways are the increasing land prices, growing tourism and increasing business and trade opportunities (Bueno et. al., 1995).
Greenways have positive effects on values of lands that are in neighboring areas. The outside recreational demands of people and increasing social interaction such as biking, walking, fishing or sightseeing cause the value of lands near to these greenways to increase (Rutgers Department of Landscape Architecture and Morris Land Conservancy, 2002).
Greenways create opportunities for economical growth, providing bicycle renting along the axis, new business areas and establishments such as shops, restaurants and health clubs.
4.4. Aesthetics benefits
Aesthetical quality and public perception can be increased by greenways. Greenways seems to be such a mechanism that provides a means of preserving open space while at the same time creating a “green infrastructure” to link people and places (Fabos, 1995). These greenways also create opportunities for planners and designers to form new norms in urban planning and design.
4.5. Recreational benefits
The greenways that are designed for recreational goals include organized sport areas, bicycle passages, walking routes, hacking courts and group activities.
These greenways as alternative transportation corridors link origins and destinations for people to go they want along the landscapes that provide sightseeing with pedestrians and cyclists (Conine et. al., 2004).
Greenways, beside developing opportunities based on natural resources in linear ways along the rural and urban landscapes, reach a dynamic recreational use, coupling the free areas that have recreational potential in urban areas on to each other. Hence a setting is prepared for both recreational diversity, user satisfaction and using potential, and providing city sustainability (Aydemir, 2004).
4.6. Social benefits
The life quality of communities is increasing due to the natural, visual value and similar characteristics of greenways. According to the research of Lee (1999), several greenways in Oakland, Chicago affect local people because of their visual characteristics. Neighboring and friendship relations of the people who use greenway is increased and so greenways became focusing points in which various activities are made (Shafer et. al., 2000).
5. Criteria that determine greenways
Five key words show the basic characteristics of corridors in the scope of "relating to planned, designed and ecological, cultural, aesthetical and sustainable space use concepts, and space networks which are managed for multipurpose, comprising linear elements" of greenways (Frischenbruder and Pellegrino, 2006).
According to this definition:
The areal shape of greenways is first linear. This characteristic of corridors provide the recreative activities like bicycle use and it provides ecological contribution by transporting material, species and nutrients in terms of wild life and cause landscape planning to have supremacy and opportunities. This characteristic is the point that the greenways differ from other landscape planning concepts.
The greenways that are an integrated system try to make association based on linking advantages beyond the spatial scales. Link is another key that defines greenways, contacting the different levels of scales and wholeness of bigger landscape.
3. The structure of multiple functions of greenways is required to be provided functional and spatial coherence of certain uses. Because of this characteristic, especially determining process of aims is important for planning of greenways. Determining and realizing targets can be hard for greenways that carry ecological, cultural, social and aesthetical aims. For example, because both aims contradict with each other and spatial and functional differences are required for a greenway protect both recreation and wild life, one of the special management or uses should be eliminated for their togetherness. The decisions that are the aims of greenways should reflect the social and cultural values and suggestions as well as environmental protection.
Greenway policy take on a complementary duty between nature protecting and economical development, beside linking to sustainable development concept. These greenways are an effort not only protecting nature but also balancing between resource use that make possible other landscape uses of people and protecting.
Greenways supply different spatial policies based on the advantage of integrated linear systems. These greenways also can be thought as complementary for comprehensive landscape and physical planning (Viles and Rosier, 2001).
6. Greenway planning
Although the actuality of greenway concept is getting increased more and more, there are some uncertainties about how these greenways are planned. Some of the greenways are planned because they have potential for their roles in biological diversity and controlling and directing the city development, and the others because they have recreational benefits. Determining the aim is especially important for planning and designing of greenways.
One of the aims of greenway planning is environmental protecting. The greenways along the river or creek sides have effective duties such as reducing the pollution stemmed from urban and agricultural irrigation, preventing soil erosion and protecting water quality (Arendt, 2004).
Planning process targets at establishing a continuous network system that support basic ecological functions, protect important natural and cultural resources and keeping sustainability of landscape. In this respect, greenway planning head for an integrated landscape planning that try to create linear networks in a sustainable frame work (Sijmons, 1990; Kerkstra and Vrijlandt, 1990; Van Buuren, 1991; Ahern, 1995).
Greenway planning began at local scale and go on at regional scale to create greenway systems (Conine et. al., 2004). Planning process take into account the networks that are taken place in a wider landscape wholeness, and linear areas. Planning also includes an approach that provides a lot of benefits because it pays attention to areal and spatial association. In this context, greenway planning process try to provide sustainable landscapes against disintegrating, space decreasing, urban development and uncontrollable change of area use (Ahern, 1995).
7. Implementation examples of greenways
7.1. The Capital Area Greenway, Raleigh, North Carolina
The Capital Area Greenway, the first comprehensive local greenway system, is not an implementation plan that is prepared by a professional planning team or specialists. This implementation is developed as a graduate project of a student in North Carolina University. The aim of the project is to protect the natural structure of Raleigh settlement. This student suggested a greenway network through all the districts of the city instead of forming only a riverside park in his project. Today, the plan implemented protects ecosystems like wetland, suggesting recreation opportunities such as race track, bicycle passage. The Capital Area greenway is a model to 35 local scale greenways in North Carolina (Fig. 5) (Little, 1995).
7.2. Lambro River Valley Greenway, Italy
Lambro river and its environment are locally chosen as an exemplary space in order to form a greenway planning approach in regional scale, in Italy. It is targeted to protect the present natural resources, historical spaces and to create recreational spaces along the Lambro river in north of Milan by this greenway. This corridor, including the dwellings that are along the river, is a basic element formed for the motorless vehicles that couple a lot of sources in the space on to the city (Toccolini et.al., 2006).
Figure 5.
The Capital Area Greenway, Raleigh, North Carolina (Little 1995).
7.3. Calgary, Fish Creek Greenway, Canada
Fish Creek river corridor which passes through Calgary city is evaluated in the scope of greenway application in 1966 and so, in 1972, it is sequestrated by local authorities to protect these greenways and to provide possibility of recreational use of them. Calgary urban greenway is approximately of 1200 hectares with a part within the urban area of Bow River with Fish Creek River Valley. Moreover, the total length of greenway is 13 km and its wide 0.8 km. Greenway forest spaces comprise pastures, river and river flood and historical spaces. Therefore, ecological characteristics are primarily taken into account in forming the corridor. Certain development centers are chosen and connections are provided between these centers in plan. Some connections are designed as bicycle and walking way. Fish Creek protect urban greenway, natural and cultural landscape values and is one of the successful implementations of greenway that meet public recreational needs (Taylor et. al., 1995).
7.4. New England Vision Plan
In this plan, to form an integrated network of greenways that combine the greenway networks of 6 states, Connecticut, Massachusetts, Maine, New Hampshire, Rhode Island and Vermont in New England region, ABD is targeted. The basic of the aim is to make sustain natural landscapes which have mountains, hills and rivers from North to South between states. When the plan that its implementation has not yet finished is completed, a greenway connections that are 57.000 km length between the wild life, recreational, historic and cultural areas mostly along river zones are provided (Fabos, 2004).
7.5. The Brooklyn - Queens Greenway, Coney Island
The aim of Brooklyn–Queens greenway planning is that ecological, cultural, recreational sources can be easily reachable and make possible various uses of it for city people (Fig. 6). Especially, wide open spaces are present for those who prefer a lot of soccer and baseball, tennis courts that are more than 100, uses that make possible various water activities along the greenway that have much rich potential in terms of recreational uses, two golf areas, two ice skate courts, funfair and passive recreations (Little, 1995).
Figure 6.
The Brooklyn - Queens Greenway
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Developing process of greenways",level:"1"},{id:"sec_3",title:"3. Greenways types",level:"1"},{id:"sec_4",title:"4. The functions and benefits of greenways",level:"1"},{id:"sec_4_2",title:"4.1. Environmental benefits",level:"2"},{id:"sec_5_2",title:"4.2. Educational benefits",level:"2"},{id:"sec_6_2",title:"4.3. Economical benefits",level:"2"},{id:"sec_7_2",title:"4.4. Aesthetics benefits ",level:"2"},{id:"sec_8_2",title:"4.5. Recreational benefits",level:"2"},{id:"sec_9_2",title:"4.6. Social benefits",level:"2"},{id:"sec_11",title:"5. Criteria that determine greenways",level:"1"},{id:"sec_12",title:"6. Greenway planning",level:"1"},{id:"sec_13",title:"7. Implementation examples of greenways",level:"1"},{id:"sec_13_2",title:"7.1. The Capital Area Greenway, Raleigh, North Carolina ",level:"2"},{id:"sec_14_2",title:"7.2. Lambro River Valley Greenway, Italy",level:"2"},{id:"sec_15_2",title:"7.3. Calgary, Fish Creek Greenway, Canada",level:"2"},{id:"sec_16_2",title:"7.4. 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1. Introduction
Breast cancer (BC) is the most common malignant tumor in women (12%) worldwide and is the second leading cause of cancer mortality after lung cancer (26%) [1].
Approximately 95–97% of tumors are estrogen-dependent in the early stages of their development [2, 3] and more than 70% express very high levels of estrogen receptor alpha (ERα) [4]. The fundamental difference of extragonadal estrogen synthesis is its autocrine nature—that an organ producing estrogens is a target organ at the same time. Thus, local concentration of estrogens in such organs may be markedly elevated. Peripheral estrogens formation is increased after menopause, and compensates estrogens deficiency in different organs and tissues [5]. Extragonadal estrogens’ production may rise with the aging. Moreover, it was continually emphasized in the literature that the increased level of estrogens in the body is considered as a risk of the BC development [6, 7].
Biologically active hormones, in particular the most active estrogen estradiol (E2), play a critical role in the initiation and development of hormone-dependent breast cancer (HDBC). In premenopausal women, estrogens are mainly (75%) synthesized in the ovaries, and thus, a luteinizing hormone-releasing hormone (LH-RH) agonist [8, 9] is useful to suppress the function of pituitary hormone. In postmenopausal women estrogens are produced in peripheral tissues such as adipose tissues, skin, and mammary glands [10, 11].
Adrenal dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and adrenal or ovarian androstenedione are also sources of E2 in peripheral tissues. In postmenopausal women, concentrations of DHEAS, DHEA, and androstenedione in plasma are relatively high; approximately 1.8, 6.6, and 1.9 nM, respectively. In contrast, plasma concentrations of estrone (E1) and (E2) are several-fold lower (70 and 30 pM, respectively) [12].
Another important steroid precursor for estrogen formation is E1-sulfate (E1S). It is the most important estrogen in the peripheral blood, with relatively high (0.6 nM) concentrations in postmenopausal women. E1S levels are associated with high body-mass index, which suggest that E1S originates from adipose tissue. Concentrations of E1S in plasma are 10–20 times higher than those of E1 and E2, as well as its half-life in the plasma is longer than the half-life of unconjugated estrogens.
Enzyme steroid sulfatase (STS) converts E1S to E1, followed by the reduction to the biologically active estrogen, E2, by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which is overexpressed in many breast tumors.
In BC tissues estrogens can be locally produced de novo by estrogen synthesis enzymes to promote tumor growth.
The level of estrogens in BC tissues of postmenopausal women can be 10–40 folds higher than in blood circulation and 5–10 times higher than in noncancerous breast tissues [13]. Furthermore, the intratumoral E2/E1 ratio is significantly higher in postmenopausal BC than in premenopausal BC. High concentrations of estrogen in breast tissue increase the risk of BC development [14, 15].
Thus, inhibition of enzymatic synthesis of estrogens is an effective therapeutic strategy for postmenopausal women with estrogen receptor-positive (ER+) tumors [16, 17]. In situ transformations of inactive steroids require activity of a series of enzymes that were found in hormone-sensitive cancers.
The scheme of estrogens formation in human body includes: (a) formation of E1 from androstenedione under the action of cytochrome P450 aromatase, (b) reduction of E1 by 17β-HSD1 leads to more active E2. Importantly, almost insoluble in aqueous media E1 is converted into water-soluble E1S under the action of sulfotransferase (STS). E1S does not possess hormonal activity, however it may be transported into various targets (Figure 1) [18, 19]. Several reviews focus on aspects of human steroidogenesis [18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29].
Figure 1.
Estrogens formation in human body.
Free hormones are formed from sulfates of estrogen and androgens under action of steroid sulfatase. At high concentrations, androgens compete for binding with ERs. The activation of ERα under the action of androstenediol and DHEA in BC cells has been detected. It is confirmed by the inhibition of cell growth in the presence of antiestrogens. The evaluation of E1S level during diagnostic of various oncological diseases (for example, prostate cancer) is of high importance [30].
2. Approaches for the manipulation of estrogen level in tumors
2.1 Endocrine therapy
Hormonal (endocrine) therapy is effectively used for the treatment of HDBC. Most types of BCs are estrogen-dependent, with approximately 55% in premenopausal women and 75% in postmenopausal women [31, 32, 33, 34].
Selective estrogen receptor modulators (SERMs) or down-regulators (SERD), such as tamoxifen, raloxifene, ospemifine, and fulvestrant are compounds that are currently used in clinical practice to treat BC [9, 35]. In breast tissues, SERMs effectively block the activation of ER(α) by endogenous ligands, preventing the transcription of genes mediated by estrogen response elements [36, 37]. SERMs have tissue-specific effects on ERα that results in antagonist activity in breast and uterus tissues as well as agonist activity in bone. Although tamoxifen and raloxifene possess the desired SERM activity, they also increase the risk of venous thromboembolism [38] and exhibit toxicity [22]. Given that resistance (de novo or acquired resistance) is a major limiting factor in the use of endocrine therapy, additional endocrine therapies with other mechanisms of action are needed [39, 40].
2.2 Inhibitors of enzymes responsible for the estrogen formation in tumors
The aromatase enzyme is responsible for the conversion of testosterone and androstenedione to E2 and E1, respectively. Thus, inhibition of the aromatase enzyme is one of the approaches for the development of new drugs to treat BC [41, 42, 43].
Nonsteroidal third-generation aromatase inhibitors (AIs), such as anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin), are often used for postmenopausal hormone-dependent BC treatment in clinical practice. Despite the success of AIs in the clinic, numerous BC patients still progress after AI therapy due to the development of resistance to AIs and side-effects such as osteoporosis caused by whole-body deprivation of estrogen [44, 45]. Mechanisms of AI resistance include ligand-independent activation of the ER and signaling via other growth factor receptors; new insights about resistance are published recently [45].
The overall response rates for AIs (40–50%) suggest the presence of alternative sources of estrogens. The production of E1, DHEA and androstenediol is an important mechanism of resistance to AI treatment [46].
It was demonstrated that AIs used sequentially with tamoxifen had higher efficacy compared to tamoxifen alone, with an improvement in overall survival [47].
There are other factors involved in tumor growth [48]. The enzymes STS and 17β-HSD1 have been identified as essential parts in E2 production and subsequent promotion of cancer growth. Recently it was shown that 17β-HSD7 also plays a key role in increasing the E2/E1 ratio in BC tumors [49]. Very recently, some evaluations of the “sulfatase pathways” in tumor stroma have been carried out [50].
The STS is also responsible for the hydrolysis of DHEAS to DHEA, which is an immediate precursor of androstenediol, a potent estrogenic steroid [51], whose formation is not influenced by AIs. DHEAS stimulates proliferation of MCF-7 cells from BC, which could be blocked by an antiestrogen or STS inhibitor but by an AI. E1S and DHEAS are particularly abundant in blood circulation and could act as a reservoir of steroid precursors, specifically in BC [29, 52]. The formation of DHEA through the STS pathway accounts for the production of 90% of the androgen androstenediol [52], which possesses estrogenic properties, that are 100-times weaker than estradiol [13, 53]. Androstenediol is present at 100-fold higher concentrations than estradiol in the circulation, and may have estrogenic properties that are equal to estradiol [54]. Thus, inhibition of STS has the dual property of reducing local androstenediol biosynthesis [55, 56].
2.3 Steroid sulfatase enzyme (STS)
The STS enzyme (EC 3.1.6.2, aryl sulfatase C, steryl-sulfatase) is widely distributed throughout the body and plays critical role in steroidogenesis [54]. Publications in recent years indicate the role of STS activity in gynecological diseases [57], mentioning diminished endometriosis in vivo under the action of STS inhibitors [58, 59]. However, a phase II trial with STS inhibitors in endometrium cancer patients with advanced disease revealed no superior effects as compared to progestin megestrol acetate, and further studies are ongoing [60]. STS inhibitors are also useful for the treatment of ovary cancers and prostate cancer [16, 61].
According to the in vitro studies, STS is the main enzyme responsible for estrogen production in hormone-dependent breast tumors, and has several hundred times higher activity in liver and normal/malignant breast tissues than aromatase [13, 53, 62]. STS mRNA expression (74%) in ERα-positive breast tumors is an independent prognostic indicator in predicting relapse-free survival, with higher levels of expression being associated with a poor prognosis [63]. Like aromatase inhibitors, sulfatase inhibition can only be used in postmenopausal women. Probably, the greatest benefit with sulfatase inhibition is in those cases where DHEAS levels are high. To date, STS inhibitors are still in an early stage of development [53, 64, 65].
The human STS is a protein, integrated in microsomal membrane. Its three-dimensional structure has been determined (PDBcode 1P49) [66]. However, knowledge about regulation of its expression as well as activity is limited. The topology of the active site of the steroid sulfatase and the arylsulfatases A and B is similar [66].
Most of the STS inhibitors discovered to date, act as irreversible active-site-directed inhibitors. An aryl sulfamate group (ArOSO2NH2) is considered as the pharmacophore for irreversible inhibition of the enzyme. One of the first time-, pH-, and concentration-dependent irreversible active-site directed-steroidal inhibitor is estrone-3-O-sulfamate (EMATE), which inhibit STS in MCF-7 cells from BC by 99% at 0.1 μM and has an IC50 value of 65 pM (IC50 = 80 nM in placental microsomes). EMATE was evaluated in clinical trials [67]. The highest effectiveness of EMATE has been demonstrated in rats (subcutaneous and oral administration). STS activity was also inhibited when EMATE was administered to humans in dose 0.5 mg/kg [68].
Despite the exceptional potency of the EMATE [67, 68], it is not used in clinical practice to treat hormone-dependent BC because metabolic conversion of EMATE by STS releases estrone, which act via estrogen receptors, and can directly promote tumor growth [69]. Nevertheless, EMATE is now the prototypical inhibitor, and used as standard during evaluation of other potential STS inhibitors [19].
2.4 Mechanisms of inactivation of steroid sulfatase
Several research groups made attempts to establish the mechanism(s) of sulfatase inactivation. However, the precise mechanism of inhibition is still uncertain. In 2010, Spillane and Malaubier have established that the hydrolysis of EMATE occurs by two different mechanisms: an SN2 mechanism below pH 9.5 and E1cB mechanisms involving N-sulfonylamines at higher pHs [70]. Detailed presumable mechanisms have been discussed in recent reviews [71, 72, 73].
Based on the mechanisms, the result of the hydrolysis is free estrone. Moreover, under per os administration, the activity of EMATE is several times higher than the activity of estrone, due slow metabolism of EMATE in liver [68]. EMATE is not subjected to metabolic inactivation in red blood cells. Thus, consideration of hormonal activity and side-effects of steroids with free phenolic group is important in the modeling of sulfatase inhibitors for therapeutic use [54, 74, 75].
The knowledge of the crystal structure opens the rational drug design of molecules for the inactivation of steroid sulfatase.
2.5 Nonsteroidal STS inhibitors
Many investigations have been carried out to develop nonsteroidal STS inhibitors, because nonsteroidal drugs and their metabolites may have less undesirable effects.
4-Methylcoumarin-7-O-sulfamate (1, Coumate) was the first time- and concentration-dependent STS inhibitor (IC50 = 380 nM) in oral dose 10 mg/kg/day, and in vivo has no estrogenic activity. 3,4-Dimethylcoumarin-7-O-sulfamate (2) was a more potent inhibitor (IC50 = 30 nM) [76].
A search of an orally active, nonestrogenic, nonsteroidal STS inhibitors among tricyclic compounds based around the coumarin core resulted in the discovery of Irosustat (667-coumate, STX64, BN83495) [77], which is the first-in-class irreversible time- and concentration-dependent STS inhibitor for the treatment of hormone-dependent BC in postmenopausal women that has been clinically evaluated in breast, endometrial, and prostate cancers [77] and there is potential for innovative dual-targeting approaches [78, 79], with an IC50 value of 8 nM in placental microsomes. The inhibitor (2) does not possess any estrogenic activity in in vitro and in vivo assays [80].
The optimum dose of 40 mg/day was estimated in phase I/II trials [81]. Efficiency of Irosustat has also been demonstrated in a phase II study in (ER+) endometrial cancer in women with advanced or recurrent disease [82]. The high bioavailability of Irosustat is explained by the prevention of degradation by sequestration inside red blood cells where it, similarly to EMATE, binds to (and inhibits) carbonic anhydrase II (IC50 = 22 nM) [83]. The inactivation mechanism suggests that a sulfamate group is transferred to the gem-diol form of formylglycine 75 of steroid sulfatase due to a facile E1cB elimination of sulfamate anion to give the corresponding coumarin, which has a long half-life in blood [84]. However, the further development of Irosustat in monotherapy was stopped in the phase I/II clinical studies, because Irosustat does not possess superior properties to the current standard of care megesterol acetate, and its relative bioavailability decreases with increasing dose. The study of its combination with other hormonal therapies (for example, with the aromatase inhibitor anastrozole) is underway [85]. Metabolism of Irosustat has been investigated [86]. Irosustat also inhibits skin and liver STS [86].
One of the first examples of the dual SERM/STS inhibitor was published by Duquesne University [87]. 4-Hydroxytamoxifen is a metabolite of main drug tamoxifen used as endocrine therapy in (ER+) BCs [88]. This metabolite is a SERM and has antiestrogen effects in breast tissues, however, acts as an estrogen agonist in other tissues such as bone marrow. The sulfamate derivative 3 of 4-hydroxytamoxifen was shown to be an STS inhibitor with Ki = 35.9 μM.
Poirier with colleagues, among tetrahydroisoquinoline-N-substituted derivatives [90], found second-generation dual-action compounds that inhibit STS and act as a SERM. These compounds are devoid of estrogenic activity and toxicity. Their sulfamate derivatives possess high inhibitory activity toward STS (IC50 of 3.9, 8.9, and 16.6 nM). Both phenolic and their sulfamate derivatives show no estrogenic activity and moderate antiestrogenic properties. All compounds significantly stimulate osteoblast-like Saos-2 cell proliferation, thus suggesting a SERM activity. The results of molecular docking experiments suggest that the most active compounds 6 and 7 bind in a competitive manner with E2 [91].
2.5.2 Dual aromatase/STS inhibitors
Another approach for the treatment of hormone-dependent BC is the development of DASIs, which may have an additive or synergistic antitumor effect. The potential advantages of a single chemical agent with the ability to interact with multiple biological targets were highlighted previously [92]. In the case of DASIs, this goal is being pursued by the introduction of the critical sulfamate unit in structures with known aromatase-inhibiting properties [93, 94]. All DASIs are still in preclinical investigations [95].
One of the best dual inhibitors is compound 8 with nonestrogenic properties. 2′,4′-Di-cyanobiphenyl-4-O-sulfamate (TZS8478) (9) also shows the best STS inhibition [96].
One of the most potent dual inhibitor is compound 10 with 98 and 85% inhibition of STS and aromatase, respectively, at 10 μM [97]. A series of DASIs have been investigated [98, 99]. Compound 11 (STX681, IC50 = 0.82 nM for aromatase and IC50 = 39 nM for STS) and similar analog 12 also exhibit an excellent profile against aromatase (IC50 = 0.13 nM) and STS (IC50 = 3.5 nM) and are not estrogenic [100]. Bissulfamate 13 at a single oral dose of 10 mg/kg inhibits aromatase and rat liver STS by 60 and 88%, respectively. The anastrazole inspired compound 12 is also potent dual inhibitor in vivo [101, 102].
Among compounds on letrozole and vorozole templates, the most potent inhibitors were compounds 15 (aromatase IC50 = 0.5 nM and STS IC50 = 5.5 nM) and 16 (IC50 = 0.0001 μM) [103]. When orally dosed, compound 15 reduces plasma estradiol levels and inhibits liver STS activity [103].
Potter with coauthors published the successful realization of the strategy when the core components of the two leading DASIs resulted in the hybrid structures that exhibit a very high level of dual inhibition against aromatase and STS in vitro (IC50 = 0.015–0.75 nM). Most active compound is analog 17 (IC50 for aromatase = 0.0002 μM, for STS = 0.0025 μM) [104].
The latest achievements in the field of nonsteroidal AIs are presented in recent reviews [105, 106].
2.6 Steroidal STS inhibitors
2.6.1 Steroid-based STS inhibitors without sulfamate group
Nonsulfamated STS inhibitors based on estrogens are weaker than EMATE. Most active STS inhibitors without sulfamate group with highest activity are represented by compounds 18, 19, and 20 (IC50 = 12, 21, and 9, respectively) [107, 108, 109].
Estradiol dimer 21 also exhibits STS inhibitory activity in nanomolar range [110]. STS inhibitors are exemplified by tetrazole derivative 22 and boronic derivative 23 [111, 112, 113].
In the series of 4-substituted 17β-arylsulfonamides of 17β-aminoestra-1,3,5(10)-trien-3-ol, compounds 24 and 25 are tight-binding inhibitors with Ki app values of 1 and 2.5 nM [114].
2.6.2 Steroid-based STS inhibitors with sulfamate group
The estrogenicity of EMATE and estradiol-3-O-sulfamate (26, E2MATE, PGL2001, J995) is the serious restriction for their development as anticancer agents. E2MATE effectively inhibits STS activity in endometrial tissue in vitro and in vivo (in doses 1.0 and 0.5 mg/kg) without affecting systemic E2 levels [58, 59, 115, 116], and is introduced into Phase IIa of clinical trials [117]. E2MATE has been also clinically investigated as a pro-drug for hormone-replacement therapy and some limited clinical data are available. EMATE and E2MATE are bound to carbonic anhydrase (for EMATE IC50 = 23 nM) within red blood cells, being dual inhibitors of carbonic anhydrases and STS [118].
The sulfamate 27 (NOMATE) was evaluated as an STS inhibitor. This steroid without the 17-carbonyl group possesses ablated estrogenicity as well as reduced STS activity compared to EMATE. NOMATE was shown to exhibit antitumor activity against a range of tumor cell lines [119].
D-ring lactone 28 has been developed as an orally available STS inhibitor [114]. The latest together with related lactam 29 were independently developed by Imperial College and University of Bath [120]. These compounds are potent STS inhibitors (98 and 91% inhibition of STS activity in MCF-7 cells at 0.1 μM, respectively; oral dose of 2 mg/kg/day) without estrogenic effects.
Simple modifications of the D-ring have led to dramatic variations in estrogenicity. Thus, the conversion of EMATE to the oxime results in a super-estrogen. From the other hand, D-ring heterocyclic derivatives exhibit reduced estrogenicity [121, 122].
The replacement of ring D with N-substituted piperidinedione moiety results in the loss of estrogenic properties and greater STS inhibitory activity in vivo compared to STX64, as it was shown by the compounds STX213 (31) [123] and STX1938 (30) [124]. The STX1938 (30) and STX213 (31) inhibit STS with IC50 of 1 nM and 35 pM correspondingly (90- and 18-fold more potent than EMATE, respectively) [125]. STX213 and STX1938 possess superior properties in comparison with STX64 in vivo models with once weekly oral dose 1 mg/kg [125, 126]. The docking studies explained the greater potency of STX1938 in comparison with STX213 by the increased lipophility of CF3 group and the ability of the fluorine atoms to participate in C-F---H-O and C-F --- H-N interactions in the STS binding site. STX213 (31) demonstrates a greater effect on tumor growth than Irosustat (oral dose 10 mg/kg/day) [21]. Most active among 17-modified EMATE derivatives as STS inhibitors was steroid 32 (IC50 = 11 pM) [126]. The saturated analog 33 possesses similar potency (IC50 = 34 pM), and is not estrogenic [126].
Among various 2- and 4-substituted and 2,4-disubstituted EMATE derivatives, most active compounds are 2-(2-prop-2-enyl)-EMATE (34, IC50 = 37 nM in MCF-7 cells) [126]; and 4-nitro-EMATE (35, IC50 = 0.01 nM in MCF-7 cells) (EMATE; IC50 = 0.83 nM in MCF-7 cells), and steroid 34 is nonestrogenic [127].
Cyclic sulfamate 36 is an effective STS inhibitor (IC50 = 9.3 nM) in vivo with dose regime 1 mg/mouse/day for 5 weeks [128]. The derivatives of oxathiazine 36 are claimed as estrogen-ablative agents; however, no data on their activity have been published [129]. Cyclic sulfamates with six-membered ring are time-dependent inactivators [130]. Acyclic mono-alkylated sulfamates are not time-dependent inactivators of sulfatases. Probably, imino compound 36 hydrolyzes to the ortho-formyl sulfamate in situ [53]. The five-membered ring compounds such as 37 are not time-dependent inactivators of STS [131].
2.6.3 Dual 17β-HSD1/STS inhibitors
17βHSD converts E1 to E2 and DHEA to androstanediol [132]. Several inhibitors based on steroidal skeleton have been successfully developed [133, 134]. Few dual inhibitors of 17β-HSD and STS for the treatment of steroid hormone-dependent diseases are patented [135]. The example of such inhibitors is represented by the compound 38.
A-ring-modified steroidal sulfamates, for example, series of 2-OMe-estradiol sulfamates and analogs have been investigated as nonestrogenic STS inhibitors [136, 137]. 2-MeO-EMATE 39 demonstrates the excellent inhibitory properties in the relation to STS in vitro (IC50 = 30 nM) and in vivo and is not estrogenic [138]. It strongly shows the antiproliferative effects toward BC cells by inducing apoptosis and cell cycle arresting in the G2/M phase [139].
2-Ethyl-EMATE 40 was identified as a promising multitargeted anticancer agent with strong ability to arrest the cell cycle, inhibit angiogenesis, as well as inhibit tumor growth in a xenograft model [140]. It was found that 2-ethylestrone (desulfamoylated compound 40) belongs to series of potent superoxide dismutase inhibitors [141].
It is known that 2-methoxyestradiol, a metabolite of E2, possesses antiangiogenic properties and prevents tumor growth through disrupting tubulin polymerization by binding at the colchicine-binding site [142, 143]. 2-Methoxyestradiol is considered as the perspective compound for the treatment of endometriosis [144].
The anticancer effects of the 2-substituted sulfamate estrogen derivatives arise from disruption of tubulin polymerization, and the compounds also binding at the colchicine site [145]. 3,17β-Bissulfamates of estrogens are other representatives of multitargeted antitumor agents, acting as STS inhibitors with antiproliferative activity (IC50 = 18–250 nM) [146]. Such bissulfamates compete with colchicine for tubulin binding and disrupt microtubules resulting into cell cycle arrest just by apoptosis in vitro and in vivo [147, 148] and inhibit angiogenesis in vitro and in vivo [149]. The STS inhibitory activity of bissulfamate 41 is comparable to EMATE activity [150]. Bissulfamoylated derivatives with 2-MeO (42, STX140) and 2-Et (44, STX243) substituents in steroidal skeleton exhibit high STS inhibitory activity (IC50 = 39 and 1000 nM, respectively) [151].
STX140 (42) and STX243 (44) possess in vivo activity also against the MDA-MB-435 cell line (at 20 mg/kg oral) [152]. STX140 in vivo inhibits MDA-MB-231 breast tumors [152, 153, 154].
Coordination of the 17-sulfamate residue to the zinc in active site of the complex of STX140 with human carbonic anhydrase II is revealed [155].
STX140 depolarizes mitochondrial bioenergetics, activates caspase 3/7 causing apoptosis through the intrinsic mitochondrial pathway, and downregulates the expression of caspase inhibitors [156]. The activity of such compounds is also explained by their ability to disrupt the tubulin-microtubule equilibrium in cells as being central to their antitumor activity. STX140 and STX243 bind with the colchicines binding site of tubulin. 2-(11C)Methoxy-3,17β-OO-bis(sulfamoyl)estradiol has been proposed as a new potential PET agent for imaging of steroid sulfatase in cancers [157].
One more example of 2-MeO-derivatives as effective STS inhibitors is illustrated by compound 45 containing cyano group at position C-17 [158].
2-Difluoromethyl-E1-3-O-sulfamate (46) is 91-fold more potent inhibitor compared to EMATE (IC50 = 0.1 and 9.1 nM, respectively) [159].
The level of STS inhibition for 17β-(N-alkylcarbamoyl)-estra-1,3,5(10)-trien-3-O-sulfamates (47) and 17β-(N-alkanoyl)-estra-1,3,5(10)-trien-3-O-sulfamates (48) is similar to or exceeded that of EMATE. Some of these compounds are nonestrogenic. 17-(N-alkylcarbamoyl)-estra-1,3,5(10)-triene-3-O-sulfamates and the inverse amides have been patented as good STS inhibitors [129].
Among a series of C17-ketone and amide-modified estrone-derived sulfamates, compound KW-2581 (49, 17-diisopropylcarbamoyl-1,3,5(10),16-estratetraen-3-yl-sulfamate) is the most promising, not estrogenic, orally active anticancer agent for the treatment of hormone-dependent BC and endometrial cancer [160]. KW-2581 as STS inhibitor is five times more potent compared to STX-64 (IC50 = 4 nM) [161]. It was also demonstrated that the compound inhibits the ability of androstanediol-S to stimulate the in vivo growth of MCF-7 cells from BC overexpressing STS. However, KW-2581 is practically insoluble in water (approx. 0.1 ng/mL). The attempts to increase its oral bioavailability showed that the milled powder exhibited poorer properties than the intact sample, including a lower level of crystallinity, higher water content, and increased decomposition rate [162].
Diverse 17α-alkylated estradiol sulfamates as STS inhibitors have been patented [163] and 17α-benzyl-derivatives have been investigated [164].
Compound EM-1913 (50) is nonestrogenic steroidal STS inhibitor with IC50 = 0.05 nM [165], which also inhibits dehydroepiandosterone sulfate action in androgen-sensitive tissues, being therefore considered as a potential drug for the treatment of prostate cancer [166].
17α-Benzyl substituent yields reversible STS inhibitors in the absence of a sulfamate group, and incorporation of an aryl sulfamate onto the A-ring results in a potent time-dependent irreversible inhibitor. The IC50 of the tert-butylbenzyl derivative 51 is low (8.3 nM); however, steroid 51 is estrogenic. A-ring substitution leads to the reduced estrogenicity. 2-Methoxyderivative 52 has an IC50 = 0.04 nM. The compound without the tert-butyl group is nonestrogenic and effective STS inhibitor in vivo [167].
In the series of A-ring thioether-modified sulfamates, the steroid 53 is 50-fold more potent inhibitor of STS than steroid 52; however, it possesses weak inhibitory activity against MCF-7 cells proliferation (IC50 = 10 μM) [168].
2.6.4 Dual STS/SERM inhibitors
Maximum estrogen blockade in the treatment of (ER+) BC may be achieved using dual ERα antagonists and STS inhibitors, which might cause osteoporosis as a side effect [169]. In this case, the compound possessing SERM properties is needed.
Thus, a novel orally available irreversible dual STS/SERM inhibitor SR16157 (NSC 732011) (60) (IC50 = 0.1 μM) has been developed as a very promising inhibitor with excellent pharmacokinetics and acceptable toxicological profile [170].
Desulfamoylation of SR16157 (54) results in SR16137 (55), which is a tissue-selective antiestrogen with beneficial effects on bone and cardiovascular system [171]. SR16157 is 10 times more potent as a growth inhibitor of MCF-7 cells than either the antiestrogens tamoxifen or SR1613. Additionally, SR16137 has a 10-fold higher affinity for ERα as compared to tamoxifen. SR16157 was shown to possess minimal genotoxic activity [172]. SR16157 has been recommended in initial phase I of clinical trials with the starting dose of 1.3 mg/kg/day administered as a single dose in humans.
We demonstrated that 8-alpha-analogs of steroid estrogens effectively inhibit the growth of BC cells, including triple negative BC [173, 174].
3. Conclusions
Manipulation of hormone biosynthesis in tumors by enzymes inhibitors is a very attractive approach for the treatment of hormone-dependent tumors such as breast, prostate cancer, and endometriosis.
The importance of STS in human body has been underlined by many investigations. Thus, STS-catalyzed hydrolysis of pregnolone-3-sulfate and dehydroepiandro-sterone-3-sulfate in the brain regulates neurosteroid synthesis and influences memory. STS inhibition for the potentiation of memory in sufferers of neurological diseases such as Alzheimer’s disease and dementia has been postulated [175]. The role of STS inhibitors as agents to reveal beneficial endogenous glucocorticoid effects was also claimed. The use of STS inhibitors in combination with the immunosuppressive ascomycin for the treatment of acne, seborrhoea, androgenetic alopecia, and hirsutism is patented. The administration of an estrogen (including norgestimate and norelgestromin), in combination with a progestogen in hormone-replacement therapy act by inhibiting STS, thus reduce estrogen production and protect the endometrium and breast from hormone-dependent cancers [176]. STS inhibitors prevent ovarian cycle disturbance, prolonged unopposed secretion of estrogens, and ovarian follicular cyst formation in premenopausal women, as well as prevent premature uterine contractions, particularly for preterm labor [177].
The importance of STS inhibition in endometriosis, prostate cancer, as well as latest discussions about mechanism of inhibition is well considered in the review of Prof. Potter [178]. The significance of steroid sulfatase and sulfotransferases in gynecological diseases are summarized in the review [57].
As far as estrogenic compounds may stimulate tumor cells growth, the main requirement for STS inhibitors and their metabolites is the absence of estrogenicity. Among nonsteroidal STS inhibitors only one nonestrogenic compound-Irosustate was evaluated in clinical trials with excellent properties, however its further development was stopped. Currently, the action of Irosustate in the combination with AIs is investigated.
The discovery of dual (multitargeted) inhibitors is the most promising nowadays. For example, several DASIs based on anastrazole, letrozole, and vorozole templates inhibit both STS and aromatase in nanomolar concentrations, being nonestrogenic; and have a chance to be introduced in clinical trials.
Among STS inhibitors based on steroid skeleton 17α-benzyl-derivatives, 17β-arylsulfonamides, and 17-diisopro-pylcarbomoyl-3-O-sulfamates exhibit the best properties, especially as multitargeted (dual) anticancer potential drugs. The same modifications result in the increased activity against STS in the case of 2-OMe-3-O-sulfamates as well as 2-OMe-3,17β-bissulfamates. The latter also possess activity against most aggressive form—triple negative BC.
Additionally, 8α-steroid estrogen analogs without estrogenic properties possess high STS activity and block BC cells growth with the activity comparable to standard of care for BC treatment tamoxifen.
Acknowledgments
The authors greatly appreciate Dr. Anna S. Chentsova for careful reading of the manuscript and her valuable comments. The reported study was funded by RFBR according to the Research Project No. 16-54-76024.
Conflict of interest
The authors confirm that this article content has no conflicts of interest.
Abbreviations
AIs
aromatase inhibitors
BC
breast cancer
COMT
catechol-O-methyltransferase
Coumate
4-methylcoumarin-7-O-sulfamate
DASI
dual aromatase-sulfatase inhibitor
DHEAS
dehydroepiandrosterone sulfate
FGly
for-mylglycine
GPER, GPR30
G-protein-coupled estrogen receptor
HDBC
hormone-dependent breast cancer
17βHSD
17β-hydroxysteroid dehydrogenase
E1
estrone
E2
estradiol
E2MATE
estradiol-3-O-sulfamate
EMATE
estrone-3-O-sulfamate
ER
estrogen receptor
LH-RH
luteinizing hormone-releasing hormone
2-OHE1
2-hydroxyestrone
4-OHE1
4-hydroxyestrone
2-OHE2
2-hydroxyestradiol
4-OHE2
4-hydroxyestradiol
STS
steroid sulfatase
SERD
selective estrogen receptor down-regulators
SERM
selective estrogen receptors modulator
UGT
UDP-glucuronosyltransferase
\n',keywords:"steroid sulfatase (STS), inhibitors, breast cancer, hormone-dependent diseases",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/66794.pdf",chapterXML:"https://mts.intechopen.com/source/xml/66794.xml",downloadPdfUrl:"/chapter/pdf-download/66794",previewPdfUrl:"/chapter/pdf-preview/66794",totalDownloads:517,totalViews:0,totalCrossrefCites:1,dateSubmitted:"May 3rd 2018",dateReviewed:"March 14th 2019",datePrePublished:"May 3rd 2019",datePublished:"February 26th 2020",dateFinished:"April 19th 2019",readingETA:"0",abstract:"Enzyme steroid sulfatase (STS) is considered as a promising therapeutic target for the treatment of hormone-dependent oncological diseases such as breast, endometrial, prostate cancers, and endometriosis. The discovery of potent and irreversible STS inhibitors stimulated huge efforts of preclinical and clinical work. Various STS inhibitors such as steroid sulfamate, steroid nonsulfamate, nonsteroidal sulfamate, and nonsteroidal nonsulfamate-based inhibitors have been developed. In the review known STS inhibitors from the point of view of their safety, side-effects and perspectives for clinical application are considered. Among STS inhibitors several dual (multitargeted) compounds have huge potential being nonestrogenic and acting in nanomolar levels on the targets. The dual aromatase-sulfatase inhibitors (DASI) approach has a great potential when a synergy between STS and aromatase inhibition is expected and, thus it could address acquired resistance mechanisms. Among STS inhibitors based on steroid skeleton 17α-benzyl-, 17β-arylsulfonamides, 17-diisopropylcarbamoyl-3-O-sulfamates exhibit the best properties, especially as dual anticancer potential drugs. The same modifications result in the increased activity against STS in 2-OMe-3-O-sulfamates as well as 2-OMe-3, 17β-bissulfamates, which are also active against triple negative breast cancer. 8α-Steroid estrogen analogs without estrogenic properties also possess high STS-inhibitory activity and block breast cancer cells growth with the activity comparable to tamoxifen.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/66794",risUrl:"/chapter/ris/66794",signatures:"Svetlana N. Morozkina and Alexander G. Shavva",book:{id:"7588",title:"Chemistry and Biological Activity of Steroids",subtitle:null,fullTitle:"Chemistry and Biological Activity of Steroids",slug:"chemistry-and-biological-activity-of-steroids",publishedDate:"February 26th 2020",bookSignature:"Jorge António Ribeiro Salvador and Maria Manuel Cruz Silva",coverURL:"https://cdn.intechopen.com/books/images_new/7588.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-516-6",printIsbn:"978-1-78985-515-9",pdfIsbn:"978-1-78985-608-8",editors:[{id:"69976",title:"Prof.",name:"Jorge António Ribeiro",middleName:null,surname:"Salvador",slug:"jorge-antonio-ribeiro-salvador",fullName:"Jorge António Ribeiro Salvador"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"66584",title:"Prof.",name:"Alexander",middleName:"Grigorievich",surname:"Shavva",fullName:"Alexander Shavva",slug:"alexander-shavva",email:"AGShavva@yandex.ru",position:null,institution:{name:"Saint Petersburg State University",institutionURL:null,country:{name:"Russia"}}},{id:"158729",title:"Prof.",name:"Svetlana",middleName:null,surname:"Morozkina",fullName:"Svetlana Morozkina",slug:"svetlana-morozkina",email:"morozkina.svetlana@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Approaches for the manipulation of estrogen level in tumors",level:"1"},{id:"sec_2_2",title:"2.1 Endocrine therapy",level:"2"},{id:"sec_3_2",title:"2.2 Inhibitors of enzymes responsible for the estrogen formation in tumors",level:"2"},{id:"sec_4_2",title:"2.3 Steroid sulfatase enzyme (STS)",level:"2"},{id:"sec_5_2",title:"2.4 Mechanisms of inactivation of steroid sulfatase",level:"2"},{id:"sec_6_2",title:"2.5 Nonsteroidal STS inhibitors",level:"2"},{id:"sec_6_3",title:"2.5.1 Dual selective estrogen receptor modulators/STS inhibitors",level:"3"},{id:"sec_7_3",title:"2.5.2 Dual aromatase/STS inhibitors",level:"3"},{id:"sec_9_2",title:"2.6 Steroidal STS inhibitors",level:"2"},{id:"sec_9_3",title:"2.6.1 Steroid-based STS inhibitors without sulfamate group",level:"3"},{id:"sec_10_3",title:"2.6.2 Steroid-based STS inhibitors with sulfamate group",level:"3"},{id:"sec_11_3",title:"2.6.3 Dual 17β-HSD1/STS inhibitors",level:"3"},{id:"sec_12_3",title:"2.6.4 Dual STS/SERM inhibitors",level:"3"},{id:"sec_15",title:"3. Conclusions",level:"1"},{id:"sec_16",title:"Acknowledgments",level:"1"},{id:"sec_19",title:"Conflict of interest",level:"1"},{id:"sec_18",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018;68(6):394-428'},{id:"B2",body:'Henderson BE, Ross R, Bernstein L. Estrogens as a cause of a human cancer: The Richard and Hinda Rosenthal Foundation award lecture. Cancer Research. 1988;48(2):246-253'},{id:"B3",body:'Lippman ME, Dickson RB, Bates S, Knabbe C, Huff K, Swain S, et al. Autocrine and paracrine growth regulation of human breast cancer. Breast Cancer Research and Treatment. 1986;7:59-70'},{id:"B4",body:'Fillmore CM, Gupta PB, Rudnick JA, Caballero S, Keller PJ, Lander ES, et al. 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Inhibition of MDA-MB-231 cell cycle progression and cell proliferation by C-2-substituted oestradiol mono- and bis-3-O-sulphamates. International Journal of Cancer. 2005;117(1):150-159'},{id:"B148",body:'Foster PA, Ho YT, Newman SP, Kasprzyk PG, Leese MP, Potter BVL, et al. 2-MeOE2bisMATE and 2-EtE2bisMATE induce cell cycle arrest and apoptosis in breast cancer xenografts as shown by a novel ex vivo technique. Breast Cancer Research and Treatment. 2008;111(2):251-260'},{id:"B149",body:'Ireson CR, Chander SK, Purohit A, Perera S, Newman SP, Parish D, et al. Pharmacokinetics and efficacy of 2-methoxyoestradiol and 2-methoxy-oestradiol-bis-sulphamate in vivo in rodents. British Journal of Cancer. 2004;90(4):932-937'},{id:"B150",body:'Leese MP, Leblond B, Smith A, Newman SP, Di Fiore A, De Simone G, et al. 2-substituted estradiol bis-sulfamates, multitargeted antitumor agents: Synthesis, in vitro SAR, protein crystallography, and in vivo activity. Journal of Medicinal Chemistry. 2006;49(26):7683-7696'},{id:"B151",body:'Peyrat J-F, Brion J-D, Alami M. Synthetic 2-methoxyestradiol derivatives: Structure-activity relationships. Current Medicinal Chemistry. 2012;19(24):4142-4156'},{id:"B152",body:'Newman SP, Foster PA, Stengel C, Day JM, Ho YT, Judde JG, et al. STX140 is efficacious in vitro and in vivo in taxane-resistant breast carcinoma cells. Clinical Cancer Research. 2008;14(2):597-606'},{id:"B153",body:'Tagg SLC, Foster PA, Leese MP, Potter BVL, Reed MJ, Purohit A, et al. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: A potential treatment for breast and prostate cancer. British Journal of Cancer. 2008;99(11):1842-1848'},{id:"B154",body:'Meyer-Losic F, Newman SP, Day JM, Reed MJ, Kasprzyk PG, Purohit A, et al. STX140, but not paclitaxel, inhibits mammary tumor initiation and progression in C3(1)/SV40 T/t-antigen transgenic mice. PLoS One. 2013;8(12):e80305'},{id:"B155",body:'Lloyd MD, Pederick RL, Natesh R, Woo LWL, Purohit A, Reed MJ, et al. Crystal structure of human carbonic anhydrase II at 1.95 Å resolution in complex with 667-coumate, a novel anti-cancer agent. The Biochemical Journal. 2005;385:715-720'},{id:"B156",body:'Foster PA, Ho YT, Newman SP, Leese MP, Potter BVL, Reed MJ, et al. STX140 and STX641 cause apoptosis via the intrinsic mitochondrial pathway and down-regulate survivin and XIAP expression in ovarian and prostate cancer cells. Anticancer Research. 2009;29(10):3751-3757'},{id:"B157",body:'Wang M, Xu K, Gao M, Miller KD, Sledge GW, Zheng QH. Synthesis of 2-(11C)methoxy-3,17β-O,O-bis(sulfamoyl)estradiol as a new potential PET agent for imaging of steroid sulfatase (STS) in cancers. Steroids. 2012;77(8-9):864-870'},{id:"B158",body:'Jourdan F, Leese MP, Dohle W, Ferrandis E, Newman SP, Chander S, et al. Structure–activity relationships of C-17-substituted estratriene-3-O-sulfamates as anticancer agents. Journal of Medicinal Chemistry. 2011;54(13):4863-4879'},{id:"B159",body:'Reed JE, Woo LWL, Robinson JJ, Leblond B, Leese MP, Purohit A, et al. 2-Difluoromethyloestrone 3-O-sulfamate, a highly potent steroid sulphatase inhibitor. Biochemical and Biophysical Research Communications. 2004;317(1):196-275'},{id:"B160",body:'Ishida H, Nakata T, Suzuki M, Shiotsu Y, Tanaka H, Sato N, et al. A novel steroidal selective steroid sulfatase inhibitor KW-2581 inhibits sulfated-estrogen dependent growth of breast cancer cells in vitro and in animal models. Breast Cancer Research and Treatment. 2007;106(2):215-227'},{id:"B161",body:'Ishida H, Sato N, Hosogi J, Tanaka H, Kuwabara T. Inactivation of recombinant human steroid sulfatase by KW-2581. The Journal of Steroid Biochemistry and Molecular Biology. 2008;108(1-2):17-22'},{id:"B162",body:'Aoki M, Nishimura H, Mimura A, Kita S, Yasuzawa T, Terada K. Identification of the degradation products of the steroid. Sulfatase inhibitor KW-2581 in jet mill-micronized powder. Journal of Pharmaceutical Sciences. 2013;102(6):1760-1772'},{id:"B163",body:'Jinbo Y, Inoue Y. Novel estradiol derivatives. PCT Int. Appl. WO2000053620; 2000'},{id:"B164",body:'Ciobanu LC, Martel C, Labrie F, Poirier D. Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase. Cancer Research. 2003;63(19):6442-6446'},{id:"B165",body:'Poirier D, Roy J, Maltais R, Ayan D. A potent inhibitor of steroid sulfatase (EM-1913) blocks tumor growth in nude mice (MCF-7 xenograft). Current Enzyme Inhibition. 2015;11(1):65-73'},{id:"B166",body:'Roy J, Lefebvre J, Maltais R, Poirier D. Inhibition of dehydroepiandrosterone sulfate action in androgen-sensitive tissues by EM-1913, an inhibitor of steroid sulfatase. Molecular and Cellular Endocrinology. 2013;376(1-2):148-155'},{id:"B167",body:'Potter BVL, Reed MJ. 17-Alkyl-linker derivatized estrogen 3-sulphamates as inhibitors of steroid sulphatase. PCT Int. Appl. WO0216393; 2002'},{id:"B168",body:'Leese MP, Leblond B, Newman SP, Purohit A, Reed MJ, Potter BVL. Anti-cancer activities of novel D-ring modified 2-substituted estrogen-3-O-sulfamates. The Journal of Steroid Biochemistry and Molecular Biology. 2005;94(1-3):239-251'},{id:"B169",body:'Imai Y, Nakamura T, Matsumoto T, Takaoka K, Kato S. Molecular mechanisms underlying the effects of sex steroids on bone and mineral metabolism. Journal of Bone and Mineral Metabolism. 2009;27(2):127-130'},{id:"B170",body:'Rausch L, Green C, Steinmetz K, Le Valley S, Catz P, Zaveri N, et al. Preclinical pharmacokinetic, toxicological and biomarker evaluation of SR16157, a novel dual-acting steroid sulfatase inhibitor and selective estrogen receptor modulator. Cancer Chemotherapy and Pharmacology. 2011;67(6):1341-1352'},{id:"B171",body:'Rasmussen LM, Zaveri NT, Stenvang J, Peters RH, Lykkesfeldt AE. A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer. Breast Cancer Research and Treatment. 2007;106(1 Suppl):191-203'},{id:"B172",body:'Doppalapudi RS, Riccio ES, Rausch LL, Shinon JA, Lee RS, Mortelmans KE, et al. Evaluation of chemopreventive agents for genotoxic activity. Mutation Research. 2007;629(2):148-160'},{id:"B173",body:'Pison U, Shavva AG, Morozkina SN. Preparation of 6-oxa-8-alpha-steroid estrogen analogues—A new group of unnatural estrogens and their use in medicine. JP Pat. Appl. JP2011503020; 2011'},{id:"B174",body:'Morozkina SN, Drozdov AS, Kovalev RA, Filatov MV, Shavva AG. Racemic 2,17β-disulfamoyloxy-3-methoxy-8α-estra-1,3,5(10)-triene as inhibitor of tumor cell proliferation of MCF-7. RU Pat. Appl. RU2562242; 2015'},{id:"B175",body:'Reddy DS. Neurosteroids: Endogenous role in the human brain and therapeutic potentials. Progress in Brain Research. 2010;186:113-137'},{id:"B176",body:'Meingassner JG. Combination of a steroid sulfatase inhibitor and ascomycin. PCT Pat. Appl. WO2006097293; 2006'},{id:"B177",body:'Loumaye E, Cayron-Elizondo V, Gotteland J-P. Use of steroid sulfatase inhibitors for the treatment of preterm labor. PCT Pat. Appl. WO2010013187; 2010'},{id:"B178",body:'Potter BVL. Steroid sulphatase inhibition via aryl sulphamates: Clinical progress, mechanism and future prospects. Journal of Molecular Endocrinology. 2018;61:T233-T252'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Svetlana N. Morozkina",address:"morozkina.svetlana@gmail.com",affiliation:'
Laboratory of Medicinal Chemistry, School of Biomedicine, Far Eastern Federal University, Russia
ITMO University, Russia
'},{corresp:null,contributorFullName:"Alexander G. Shavva",address:null,affiliation:'
Laboratory of Medicinal Chemistry, School of Biomedicine, Far Eastern Federal University, Russia
ITMO University, Russia
'}],corrections:null},book:{id:"7588",title:"Chemistry and Biological Activity of Steroids",subtitle:null,fullTitle:"Chemistry and Biological Activity of Steroids",slug:"chemistry-and-biological-activity-of-steroids",publishedDate:"February 26th 2020",bookSignature:"Jorge António Ribeiro Salvador and Maria Manuel Cruz Silva",coverURL:"https://cdn.intechopen.com/books/images_new/7588.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-516-6",printIsbn:"978-1-78985-515-9",pdfIsbn:"978-1-78985-608-8",editors:[{id:"69976",title:"Prof.",name:"Jorge António Ribeiro",middleName:null,surname:"Salvador",slug:"jorge-antonio-ribeiro-salvador",fullName:"Jorge António Ribeiro Salvador"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"268043",title:null,name:"Miljana Z.",middleName:"Z",surname:"Jovandaric",email:"rrebecca080@gmail.com",fullName:"Miljana Z. Jovandaric",slug:"miljana-z.-jovandaric",position:null,biography:"Miljana Z. Jovandaric was born in Serbia. She graduated from the Faculty of Medicine, University of Belgrade, Serbia, in 1989, and completed a specialization in Pediatrics at the University Children\\'s Hospital, Belgrade, in 1999. She completed her specialization in Neonatology in 2003. Dr. Jovandaric completed her master’s thesis on “Analysis of lipid infants of women suffering from gestational diabetes mellitus (GDM)” in 2006 and her doctoral dissertation on “Effect of hypoxia on electrolyte and lipid levels in term newborns” in 2018, both at the School of Medicine, University of Belgrade. She is the author and co-author of eighty-four scientific papers presented at national and international conferences and published in scientific journals. Dr. Jovandaric is currently head of the Department of Sick Newborns at the Clinic for Gynecology and Obstetrics, Department of Neonatology, Clinical Centre of Serbia.",institutionString:"Clinical Center of Serbia",profilePictureURL:"https://mts.intechopen.com/storage/users/268043/images/system/268043.png",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"4",totalEditedBooks:"2",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:{name:"Klinički centar Srbije",institutionURL:null,country:{name:"Serbia"}}},booksEdited:[{type:"book",slug:"veganism-a-fashion-trend-or-food-as-a-medicine",title:"Veganism",subtitle:"a Fashion Trend or Food as a Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/8158.jpg",abstract:"Veganism is a way of eating and living that avoids using animals and their products for food, clothing, and other purposes. Vegans do not consume meat, fish, seafood, eggs, honey, and dairy products, nor do they wear or carry items made of fur, wool, leather, and other materials of animal origin. Many vegans also avoid animal-tested products.",editors:[{id:"268043",title:null,name:"Miljana Z.",surname:"Jovandaric",slug:"miljana-z.-jovandaric",fullName:"Miljana Z. Jovandaric"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",title:"Edited Volume"}},{type:"book",slug:"childbirth",title:"Childbirth",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/9160.jpg",abstract:"In 2015, there were about 135 million births globally. Each year, complications from pregnancy and childbirth result in about 500,000 maternal deaths, 7 million women have serious long-term problems, and 50 million women have negative health outcomes following delivery. Most of these occur in the developing world. This book discusses many aspects of childbirth and provides recommendations for improving maternal and fetal health. Chapters covers such topics as placental abruption, induced labor, low birth weight, prenatal education programs, and improving the birth space. Authors examine effects of air pollution, consanguineous marriage, and the use of traditional birth attendants on maternal morbidity and mortality.",editors:[{id:"268043",title:null,name:"Miljana Z.",surname:"Jovandaric",slug:"miljana-z.-jovandaric",fullName:"Miljana Z. Jovandaric"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",title:"Edited Volume"}}],chaptersAuthored:[{title:"Maternal and Neonatal Outcome of Pregnancies with Autoimmune Myasthenia Gravis",slug:"maternal-and-neonatal-outcome-of-pregnancies-with-autoimmune-myasthenia-gravis",abstract:"Myasthenia gravis (MG) is an autoimmune neuromuscular disease manifested by the weakness and fatigue in skeletal muscles of the face and extremities. Transient neonatal myasthenia gravis is an uncommon type of MG affecting the newborns with mothers who suffer from the disorder or specific circulating autoantibodies. In most cases, the intensity of transient neonatal MG is not associated with the mothers’ condition but rather with maternal antibody titers. The symptoms of transient neonatal MG are hypotonia, feeding difficulties, weak cry, facial diplegia, and breathing difficulties in the affected newborns. The disease is connected to the passive transplacental transfer of anti-acetylcholine receptor antibodies (anti-AChR) or antimuscle-specific tyrosine kinase antibodies (anti-MuSK) from the affected mother to the infant. The postsynaptic neuromuscular junction is damaged by the circulation of autoimmune antibodies, and the antibodies directed against fetal AChR are responsible for the form of fetal onset. Monitoring of these newborns is necessary in the first 7 days upon birth, since during this period of life, TNM symptoms can be detected, especially on the second day. In pregnancy period, myasthenia gravis symptoms may vary and they frequently worsen, sometimes leading to premature delivery.",signatures:"Miljana Z. Jovandaric and Svetlana J. Milenkovic",authors:[{id:"268043",title:null,name:"Miljana Z.",surname:"Jovandaric",fullName:"Miljana Z. Jovandaric",slug:"miljana-z.-jovandaric",email:"rrebecca080@gmail.com"},{id:"275297",title:"Dr.",name:"Svetlana",surname:"J. Milenkovic",fullName:"Svetlana J. Milenkovic",slug:"svetlana-j.-milenkovic",email:"ceca.milenkovic@yahoo.com"}],book:{title:"Selected Topics in Myasthenia Gravis",slug:"selected-topics-in-myasthenia-gravis",productType:{id:"1",title:"Edited Volume"}}},{title:"Placenta Abruption and Delivery Method",slug:"placenta-abruption-and-delivery-method",abstract:"Placental abruption is a significant contributor to maternal mortality worldwide. Early and skilled medical intervention is needed to ensure a good outcome, and this is not available in many parts of the world. Abruptio placentae are defined as the premature separation of the placenta from the uterus. Placental abruption must be considered whenever bleeding is encountered in the second half of pregnancy, since it is a significant cause of third-trimester bleeding associated with fetal and maternal morbidity and mortality. If the bleeding persists, fetal and maternal distress may develop. Fetal and maternal death may occur if appropriate interventions are not undertaken. The severity of fetal distress correlates with the degree of placental separation. In near-complete or complete abruption, fetal death is inevitable unless an immediate cesarean delivery is undertaken.",signatures:"Miljana Z. Jovandaric and Svetlana J. Milenkovic",authors:[{id:"268043",title:null,name:"Miljana Z.",surname:"Jovandaric",fullName:"Miljana Z. Jovandaric",slug:"miljana-z.-jovandaric",email:"rrebecca080@gmail.com"},{id:"275297",title:"Dr.",name:"Svetlana",surname:"J. Milenkovic",fullName:"Svetlana J. Milenkovic",slug:"svetlana-j.-milenkovic",email:"ceca.milenkovic@yahoo.com"}],book:{title:"Childbirth",slug:"childbirth",productType:{id:"1",title:"Edited Volume"}}},{title:"Significance of Lipid and Lipoprotein in Organism",slug:"significance-of-lipid-and-lipoprotein-in-organism",abstract:"Lipids are important energy and building compounds. Their decomposition provides a significant amount of energy required for various life processes. It can thus be deposited in triglycerides and adipocytes. Some of them, in conjunction with proteins, form the most important structural elements of cells and cellular organelles, while others are precursors for the synthesis of numerous active compounds such as some hormones or prostaglandins. Lipids are ingested but can also be synthesized in the body. In circulation, lipids are found packed in lipoprotein molecules because they are insoluble in water. Lipoproteins have a central lipid part (nucleus) containing triglycerides and cholesterol esters, and on the surface there is a sheath composed of certain proteins (apoproteins), phospholipids, and small amounts of free cholesterol. Thanks to this sheath, lipids can be transported via blood. It took a long time to determine the importance and role of lipids in the body, as well as their role in many metabolic disorders of various diseases. This field is still unexplored and is a challenge for many researchers to prevent and treat lipid metabolism disorders.",signatures:"Miljana Z. Jovandaric and Svetlana J. Milenkovic",authors:[{id:"268043",title:null,name:"Miljana Z.",surname:"Jovandaric",fullName:"Miljana Z. Jovandaric",slug:"miljana-z.-jovandaric",email:"rrebecca080@gmail.com"},{id:"275297",title:"Dr.",name:"Svetlana",surname:"J. Milenkovic",fullName:"Svetlana J. Milenkovic",slug:"svetlana-j.-milenkovic",email:"ceca.milenkovic@yahoo.com"}],book:{title:"Apolipoproteins, Triglycerides and Cholesterol",slug:"apolipoproteins-triglycerides-and-cholesterol",productType:{id:"1",title:"Edited Volume"}}},{title:"Veganism: A New Approach to Health",slug:"veganism-a-new-approach-to-health",abstract:"The word vegan was given by Donald Watson in 1944 in Leicester, England, who, together with several other members of the Vegetarian Society, wanted to establish a group of vegetarians who did not consume milk or dairy products. When the proposal was rejected, Watson and like-minded people founded The Vegan Society, which advocated a complete plant-based diet, excluding meat, fish, eggs, milk and dairy products (cheese, butter) and honey. Vegans do not wear fur items, wool, bone, goat, coral, pearl or any other material of animal origin. According to surveys, vegans make up between 0.2% and 1.3% of the US population and between 0.25% and 7% of the UK population. Vegan foods contain lower levels of cholesterol and fat than the usual diet.",signatures:"Miljana Z. Jovandaric",authors:[{id:"268043",title:null,name:"Miljana Z.",surname:"Jovandaric",fullName:"Miljana Z. Jovandaric",slug:"miljana-z.-jovandaric",email:"rrebecca080@gmail.com"}],book:{title:"Veganism",slug:"veganism-a-fashion-trend-or-food-as-a-medicine",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"28404",title:"Prof.",name:"Asher",surname:"Ornoy",slug:"asher-ornoy",fullName:"Asher Ornoy",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"30993",title:"Prof.",name:"Isam Jaber",surname:"Al-Zwaini",slug:"isam-jaber-al-zwaini",fullName:"Isam Jaber Al-Zwaini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30993/images/system/30993.jpeg",biography:"Professor Isam Jaber AL-Zwaini was born on 4 January 1963, in Baghdad, Iraq. After graduating from AL-Mustansiryia College of Medicine in 1987, he worked as a house officer in different hospitals in Baghdad for 15 months, followed by military services for 3 years. He started his pediatric study in 1991 and gained the Fellowship of Iraqi Commission for Medical Specializations in 1996. He worked as a lecturer in the Department of Pediatrics, AL-Anbar Medical College, from 1996 to 2001 when he obtained the title of Assistant Professor. In 2005, he began working in the Department of Pediatrics at AL-Kindy Medical College, University of Baghdad and obtained the title of Professor in 2008. He became an associate member of the Royal College of Pediatrics and Child Health, UK, in 2007. He served as head of the pediatric department at AL-Anbar and AL-Kindy Medical Colleges for many years. He has published more than thirty scientific papers in different pediatric fields and has a special interest in pediatric hematology, neurology, and nutrition",institutionString:"University of Baghdad",institution:{name:"University of Baghdad",institutionURL:null,country:{name:"Iraq"}}},{id:"67629",title:"Dr.",name:"Zivanit",surname:"Ergaz",slug:"zivanit-ergaz",fullName:"Zivanit Ergaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Hadassah Medical Center",institutionURL:null,country:{name:"Israel"}}},{id:"254143",title:"Dr.",name:"Adel",surname:"A. Kareem",slug:"adel-a.-kareem",fullName:"Adel A. Kareem",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"269137",title:"Dr.",name:"Zeynep",surname:"Özdemir",slug:"zeynep-ozdemir",fullName:"Zeynep Özdemir",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/269137/images/system/269137.jpg",biography:"Date of Birth: 14.05.1985\nNationality:\tTurkish\n\nEducation\nPostgraduate (PhD): Gazi University – Ankara/TURKEY\nİnönü University Faculty of Pharmacy– Malatya/TURKEY, Faculty of Pharmacy, Department of Pharmaceutical Chemistry- 2010-2014\n\t \nPostgraduate (Master): İnönü University Faculty of Pharmacy– Malatya/TURKEY\nFaculty of Pharmacy, Department of Pharmaceutical Chemistry- 2007-2010\n\nGraduate: İnönü University – Malatya/TURKEY, Faculty of Pharmacy – 2003-2007\n\nWork Experience\nAssistant Proessor: İnönü University – Malatya/TURKEY, Faculty of Pharmacy – 2014-\nResearch Assistant: İnönü University – Malatya/TURKEY, Faculty of Pharmacy – 2008-2014\n\nResearch Area: Cholinesterase Inhibitors, 3(2H) pyridazinone derivatives, Antifungal and antimicrobial active azole derivatives, Anticonvulsant Drugs",institutionString:"İnönü University",institution:null},{id:"275297",title:"Dr.",name:"Svetlana",surname:"J. Milenkovic",slug:"svetlana-j.-milenkovic",fullName:"Svetlana J. Milenkovic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275297/images/12334_n.jpg",biography:"Dr. Svetlana Milenkovic was born in 1960. In 1983, she graduated from School of Medicine, University of Belgrade, and received her M.D. Later on (1992), she did her specialization in Pediatrics, and her Postgraduate in endocrinology (School of Medicine, University of Belgrade, 1998). Dr. Milenkovic, did her subspecialization in Neonatology in 2018, and defended her Doctorial dissertation in 2017 (School of Medicine, University of Belgrade). From 1983-2001 she was acting as MD and pediatrician working at Health Center Bor. In 1990 until 1992 she was a Resident in pediatics, at the Institute for Mother and Child, Belgrade. At the Clinical- Hospital Center Zemun, Belgrade, she worked as a Pediatrician, in the Department of Neonatology (2001-2008). Dr. Milenkovic was also a Resident in neonatology, at the University Children's Hospital, Belgrade and Institute for Neonatology, Belgrade (2005-2006); and in 2007 a Resident in School of Ultrasound, University Children'ss Hospital, Belgrade. From December 2008, she is working as a Neonatologist at Clinic for Obstetrics and Gynecology, Clinical Center Serbia, Belgrade, Serbia. Since 1998, Dr. Milenkovic has been a member of Pediatric Chapter of Serbian Medical Society. Her research interest include: Neonatal nutrition, Neonatal endocrinology and metabolism, and Ultrasound investigations in neonatology. Dr. Milenkovic has participated in numerous congresses and meetings, and presented posters and oral presentations. She has several published articles in different medical journals.",institutionString:"Clinical Center of Serbia",institution:null},{id:"281888",title:"Dr.",name:"Mehmet Abdullah",surname:"Alagöz",slug:"mehmet-abdullah-alagoz",fullName:"Mehmet Abdullah Alagöz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/281888/images/system/281888.jpg",biography:"Date of Birth: 16.10.1984\nNationality: Turkish\n\nEducation\nPostgraduate (PhD): Gazi University – Ankara/TURKEY\nİnönü University Faculty of Pharmacy– Malatya/TURKEY, Faculty of Pharmacy, Department of Pharmaceutical Chemistry- 2011-2017\n\t \nPostgraduate (Master): İnönü University Faculty of Pharmacy – Malatya/TURKEY, Faculty of Pharmacy, Department of Pharmaceutical Chemistry- 2008-2011\n\nGraduate: İnönü University – Malatya/TURKEY, Faculty of Pharmacy – 2004-2008\n\nWork Experience\nAssistant Proessor: İnönü University – Malatya/TURKEY, Faculty of Pharmacy – 2017-\n\nResearch Assistant: İnönü University – Malatya/TURKEY, Faculty of Pharmacy – 2009-2013\n\nResearch Area: Pyrazole derivatives, Antifungal and antimicrobial active azole derivatives, Anticonvulsant Drugs, Anticancer drugs",institutionString:"İnönü University",institution:null},{id:"290805",title:"Mrs.",name:"Liza",surname:"Weinstein-Fudim",slug:"liza-weinstein-fudim",fullName:"Liza Weinstein-Fudim",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"301191",title:"Dr.",name:"Matilde",surname:"Fernández Fernández-Arroyo",slug:"matilde-fernandez-fernandez-arroyo",fullName:"Matilde Fernández Fernández-Arroyo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/301191/images/8469_n.png",biography:'Matilde Fernández y Fernández-Arroyo, RN, CNM, LPsy, MsN, PhD\nMatilde Fernández y Fernández-Arroyo, Nurse(1983), Midwife (1985), Phycologist (1998), Sexuality Master (2000), Educational PhD (2012), is a Professor Midwifery Program at Maternity Unit, La Paz Hospital University, Madrid, and Associate Professor at Pontificia Comillas University, San Juan de Dios School of Nursing (Spain). She hasparticipated in over 40 post graduate programs and workshops.\nWorked in clinical for 13 years, in primary attention for 6 years, and from 1994 to nowadays teaching nurses and midwifes; specialized in human sexuality, women education programs and newborn cares, very interested in the education of women in health care and training of health professionals in care of women and newborn.\nShe is Madrid government´s advisor for health education, accreditation programs, and examination faculty in country official exams for midwifes vacancies at Health Public System.\nShe counts with over 50 communications in national and international meetings and congress; recognized author of many publications, especially in Spanish language, indexed by Spanish Index, also collaborator in magazines for parents (Ser Padres, MiBebé y yo, Spanish original).\nThe last indexed publication counts with great repercussion in educational circles, Assessment of the Pregnancy Education Programme with questionnaire \\"EDUMA2\\" in Madrid (Spain), 2014 by Journal Evaluation of Clinical Practice.',institutionString:null,institution:{name:"Comillas Pontifical University",institutionURL:null,country:{name:"Spain"}}},{id:"306183",title:"Dr.",name:"Radim J.",surname:"Sram",slug:"radim-j.-sram",fullName:"Radim J. Sram",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"unsubscribe-successful",title:"Unsubscribe Successful",intro:"
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